1. Project profile

Modality: Dual target small molecule inhibitor

Target: PARP7、PARP12

Indications: Lung cancer, Colorectal cancer

Research phase: PCC

Cooperation demands: license out

Mechanism of action

PARP7 is a negative regulator of cytosolic nucleic acid sensing in tumor cells.Inhibition of PARP7 can restore the signal response of type I interferon (IFN) to cytosolic nucleic acid, inhibit cell proliferation and activate the immune system, and contribute to tumor regression;

Inhibition of PARP12 inactivates AKT, thereby enhancing FOXO1 activity and inducing tumor cell apoptosis. Besides，PARP12 inhibition blocks downstream signaling of mutant KRAS, exerting cytotoxic effects on KRAS-mutant tumors；

3. Data and results

Asset exhibits broad-spectrum inhibitory activity against tumor cell proliferation，and especially show excellent activity against KRAS-mutant tumors;

Asset elicits tumor regression as monotherapy in NCI-H1373 human lung cancer xenograft model;

Asset in combination with anti-PD-1 antibody elicits tumor regression;

Following 14-day repeated oral gavage of Asset at 300 mg/kg in SD rats, no abnormal findings were observed in clinical observations, body weight, food consumption, gross necropsy, hematology, or serum biochemistry parameters compared with the vehicle control group. The no observed adverse effect level (NOAEL) was determined to be 300 mg/kg;